Eosinophilic esophagitis (EE) is an emerging worldwide disease that mimics gastroesophageal reflux disease (GERD) and can lead to esophageal narrowing and stricture. We have recently established that the esophagus is normally devoid of eosinophils, and that esophageal eosinophilia occurs in association with T helper type 2 (Th2) allergic responses in the lung and gastrointestinal tract. Employing genome wide microarray expression profile analysis, we recently discovered that the eosinophil chemoattractant and activating factor eotaxin-3 was the single most dysregulated gene in the esophagus of EE patients. Notably, levels of eotaxin-3 strongly correlated with disease severity and a single nucleotide polymorphism (SNP) in the eotaxin-3 gene was associated with disease susceptibility. Additionally, mice harboring a genetic deletion in the eotaxin receptor (CCR3) were protected from esophageal eosinophilia. Furthermore, we have established a strong association between the Th2 cytokine IL-13 (a cytokine known to induce eotaxin-3) and EE. In particular, delivery of intratracheal IL-13 or overexpression of the IL-13 lung transgene induces experimental EE in mice. We have also demonstrated that IL-13 is required for allergen-induced experimental EE, at least in part. Notably, we have shown that the human EE esophagus overexpresses IL- 13, and has a transcript profile that greatly overlaps with the esophagus from IL-13 transgenic mice. These and other findings have led us to hypothesize that a primary event in EE pathogenesis involves IL-13-driven pathology including overproduction of eotaxin-3 by esophageal epithelial cells. We propose 3 aims designed to understand the overproduction of IL-13 in EE, the mechanism by which IL-13 delivers its effects in the esophagus, and the role of eosinophils and signaling molecules in IL-13-induced experimental EE. These studies are aimed at providing a mechanistic understanding of the pathogenesis of a poorly understood disorder. These studies are timely given the recent attention that EE is receiving in the medical community and the emergence of anti-IL-13 and anti-eotaxin-3/CCR3 therapeutics that may have the potential to provide targeted therapy for EE. Layperson: Eosinophilic esophagitis is a growing medical problem that involves allergic inflammatory problems in the esophagus. The goal of this grant is to understand the mechanism of this disease by focusing on a specific molecule called IL-13.